A MYC and RAS co-activation signature in localized prostate cancer drives bone metastasis and castration resistance

Arriaga, Juan Martín; Panja, Sukanya; Alshalalfa, Mohammed; Zhao, Junfei; Zou, Min; Giacobbe, Arianna; Madubata, Chioma J.; Kim, Jaime Yeji; Rodrı́guez, Antonio; Coleman, Ilsa M.; Virk, Renu K.; Hibshoosh, Hanina; Ertunç, Onur; Ozbek, Büşra; Fountain, Julia; Karnes, R. Jeffrey; Luo, Jun; Antonarakis, Emmanuel S.; Nelson, Peter S.; Feng, Felix Y.; Rubin, Mark A.; Marzo, Angelo M. De; Rabadán, Raúl; Sims, Peter A.; Mitrofanova, Antonina; Abate‐Shen, Cory

doi:10.1038/s43018-020-00125-0

Cited by 66 publications

(60 citation statements)

References 61 publications

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“…Signaling through KRAS has long been known to impact MYC expression (45,46,67,68), and thus our results are consistent with a model in which elevated MYC activityas a result of MYC and/or KRAS amplification, or some other mechanism enhances metastatic activity. This interpretation is consistent with recent studies of lung, breast, and prostate cancers identifying a link between MYC amplification and brain or bone metastasis (37,38,69).…”

Section: Discussionsupporting

confidence: 92%

MYCcontrols metastatic heterogeneity in pancreatic cancer

Maddipati

Baslan

et al. 2021

Preprint

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The degree of metastatic disease varies widely amongst cancer patients and impacts clinical outcomes. However, the biological and functional differences that drive the extent of metastasis are poorly understood. We analyzed primary tumors and paired metastases using a multi-fluorescent lineage-labeled mouse model of pancreatic ductal adenocarcinoma (PDAC) – a tumor type where most patients present with metastases. Genomic and transcriptomic analysis revealed an association between metastatic burden and gene amplification or transcriptional upregulation of MYC and its downstream targets. Functional experiments showed that MYC promotes metastasis by recruiting tumor associated macrophages (TAMs), leading to greater bloodstream intravasation. Consistent with these findings, metastatic progression in human PDAC was associated with activation of MYC signaling pathways and enrichment for MYC amplifications specifically in metastatic patients. Collectively, these results implicate MYC activity as a major determinant of metastatic burden in advanced PDAC.

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Section: Discussionsupporting

confidence: 92%

MYCcontrols metastatic heterogeneity in pancreatic cancer

Maddipati

Baslan

et al. 2021

Preprint

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“…Importantly, our analyses exposed a subtype of primary prostate cancer characterized by divergent AR (low) and MYC (high) transcriptional signatures that are predisposed to fail standard-of-care therapies and progress to the mCRPC stage (Figure 5). Arriaga and colleagues have recently reported a MYC and RAS co-activation signature associated with metastatic progression and failure to anti-androgen treatments 51 . It is thus tempting to speculate that MYC decreases the reliance of prostate cancer cells on the canonical AR transcriptional program, therefore facilitating resistance to AR-targeted therapies.…”

Section: Discussionmentioning

confidence: 99%

MYC drives aggressive prostate cancer by disrupting transcriptional pause release at androgen receptor targets

Qiu

Boufaied

Hallal

et al. 2021

Preprint

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ABSTRACTc-MYC (MYC) is a major driver of prostate cancer tumorigenesis and progression. Although MYC is overexpressed in both early and metastatic disease and associated with poor survival, its impact on prostate transcriptional reprogramming remains elusive. We demonstrate that MYC overexpression significantly diminishes the androgen receptor (AR) transcriptional program (the set of genes directly targeted by the AR protein) in luminal prostate cells without altering AR expression. Importantly, analyses of clinical specimens revealed that concurrent low AR and high MYC transcriptional programs accelerate prostate cancer progression toward a metastatic, castration-resistant disease. Data integration of single-cell transcriptomics together with ChIP-seq revealed an increased RNA polymerase II (Pol II) promoter-proximal pausing at AR-dependent genes following MYC overexpression without an accompanying deactivation of AR-bound enhancers. Altogether, our findings suggest that MYC overexpression antagonizes the canonical AR transcriptional program and contributes to prostate tumor initiation and progression by disrupting transcriptional pause release at AR-regulated genes.STATEMENT OF SIGNIFICANCEAR and MYC are key to prostate cancer etiology but our current understanding of their interplay is scarce. Here we show that the oncogenic transcription factor MYC can pause the transcriptional program of the master transcription factor in prostate cancer, AR, while turning on its own, even more lethal program.

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“…Genome-wide correlation studies were performed and found 559 genes positively correlating with Myc expression, 93% of which correlated with Ras activation. Confronting this signature on established bone metastasis signatures let to the identification of a 16-gene signature that was based on a univariable Cox proportional hazard model based on 336 metastasis-free TCGA patients [ 90 ]. This analysis was also supported by single cell sequencing of bone metastatic versus primary prostate tumors.…”

Section: Multi-omics and Evolutionmentioning

confidence: 99%

Derivation and Application of Molecular Signatures to Prostate Cancer: Opportunities and Challenges

Doultsinos

Mills

2021

Cancers

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Prostate cancer is a high-incidence cancer that requires improved patient stratification to ensure accurate predictions of risk and treatment response. Due to the significant contributions of transcription factors and epigenetic regulators to prostate cancer progression, there has been considerable progress made in developing gene signatures that may achieve this. Some of these are aligned to activities of key drivers such as the androgen receptor, whilst others are more agnostic. In this review, we present an overview of these signatures, the strategies for their derivation, and future perspectives on their continued development and evolution.

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A MYC and RAS co-activation signature in localized prostate cancer drives bone metastasis and castration resistance

Cited by 66 publications

References 61 publications

MYCcontrols metastatic heterogeneity in pancreatic cancer

MYCcontrols metastatic heterogeneity in pancreatic cancer

MYC drives aggressive prostate cancer by disrupting transcriptional pause release at androgen receptor targets

Derivation and Application of Molecular Signatures to Prostate Cancer: Opportunities and Challenges

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